JP2011178753A - Pharmaceutical composition containing quinazolin compound as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a quinazolin compound as an active ingredient, which is useful as a cell proliferation inhibitor for cancers etc. <P>SOLUTION: The pharmaceutical composition includes a quinazolin compound represented by formula (I), (wherein R<SP>1</SP>represents a hydrogen atom or various kinds of substituents, one of groups R<SP>2</SP>and R<SP>3</SP>represents -C(OH)(Ar)R<SP>4</SP>(wherein Ar represents an aryl group or an aromatic heterocyclic group, and R<SP>4</SP>represents a hydrogen atom, an alkyl group, an aryl group, etc.), and the other group has the same meaning as R<SP>1</SP>), or a pharmaceutically acceptable salt thereof as an active ingredient. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition containing a quinazoline compound or a pharmacologically acceptable salt thereof as an active ingredient, and in particular, a quinazoline compound having cell growth inhibitory activity such as cancer or a pharmacologically acceptable salt thereof. It is related with the pharmaceutical composition which contains the salt made as an active ingredient.

  Conventionally, the following formula (A)

(In the formula, Ar ^A represents a phenyl group or a phenyl group or a furyl group substituted with a chlorine group, a bromine atom, or a methoxy group, R ^A represents a methyl group, a phenyl group, or a benzyl group, and R ^B represents Represents a hydrogen atom or a phenyl group)
The α, α-disubstituted-4-quinazoline methanol compound represented by the formula is known (for example, see Non-patent Document 1), but its pharmacological activity is not known.

Chem. Pharm. Bull. 46, 199-206 (1998)

  An object of the present invention is to provide a pharmaceutical composition containing a certain quinazoline compound, particularly a pharmaceutical composition useful as a cell growth inhibitor for cancer and the like.

  As a result of continuing screening for the pharmacological action of various compounds synthesized so far, the present inventors have found that α-substituted- or α, α-disubstituted- substituted with at least an aryl group or an aromatic heterocyclic group. It has been found that certain quinazoline compounds having a hydroxymethyl group as a substituent have an effect of inhibiting cell growth such as cancer, and the present invention has been completed.

｛式中、
Ｒ^１は、同一又は異なって、水素原子、置換若しくは非置換アルキル基、置換若しくは非置換シクロアルキル基、置換若しくは非置換アルケニル基、置換若しくは非置換アルキニル基、置換若しくは非置換脂環式複素環基、置換若しくは非置換脂環式複素環アルキル基、置換若しくは非置換アリール基、置換若しくは非置換アラルキル基、置換若しくは非置換芳香族複素環基、置換若しくは非置換芳香族複素環アルキル基、ＣＯＲ^１１（式中、Ｒ^１１は、水素原子、置換若しくは非置換アルキル基、置換若しくは非置換シクロアルキル基、置換若しくは非置換アルケニル基、置換若しくは非置換アルキニル基、置換若しくは非置換脂環式複素環基、置換若しくは非置換脂環式複素環アルキル基、置換若しくは非置換アリール基、置換若しくは非置換アラルキル基、置換若しくは非置換芳香族複素環基又は置換若しくは非置換芳香族複素環アルキル基を表す）、ＣＯＯＲ^１２（式中、Ｒ^１２は、前記Ｒ^１１と同義である）、Ｃ（＝Ｑ^１）ＮＲ^１３Ｒ^１４［式中、Ｑ^１は、酸素原子、硫黄原子又はＮＲ^１５（式中、Ｒ^１５は、前記Ｒ^１１と同義である）を表し、Ｒ^１３及びＲ^１４は、同一又は異なって、水素原子、置換若しくは非置換アルキル基、置換若しくは非置換シクロアルキル基、置換若しくは非置換アルケニル基、置換若しくは非置換アルキニル基、置換若しくは非置換脂環式複素環基、置換若しくは非置換脂環式複素環アルキル基、置換若しくは非置換アリール基、置換若しくは非置換アラルキル基、置換若しくは非置換芳香族複素環基、置換若しくは非置換芳香族複素環アルキル基、又は、Ｒ^１３とＲ^１４が一緒になって、含窒素複素環基を表す］、ＯＲ^１６（式中、Ｒ^１６は、前記Ｒ^１１と同義である）、ＯＣＯＲ^１７（式中、Ｒ^１７は、前記Ｒ^１１と同義である）、Ｓ（Ｏ）ｐＲ^１８（式中、ｐは、０、１又は２を表し、Ｒ^１８は、前記Ｒ^１１と同義である）、ＳＯ_２ＮＲ^１９Ｒ^２０（式中、Ｒ^１９及びＲ^２０は、同一又は異なって、それぞれ前記Ｒ^１３及びＲ^１４と同義である）、ＮＲ^２１Ｒ^２２［式中、Ｒ^２１及びＲ^２２は、同一又は異なって、水素原子、置換若しくは非置換アルキル基、置換若しくは非置換シクロアルキル基、置換若しくは非置換アルケニル基、置換若しくは非置換アルキニル基、置換若しくは非置換脂環式複素環基、置換若しくは非置換脂環式複素環アルキル基、置換若しくは非置換アリール基、置換若しくは非置換アラルキル基、置換若しくは非置換芳香族複素環基、置換若しくは非置換芳香族複素環アルキル基、ＣＯＲ^２３（式中、Ｒ^２３は、前記Ｒ^１１と同義である）、ＣＯＯＲ^２４（式中、Ｒ^２４は、前記Ｒ^１１と同義である）、ＳＯ_２Ｒ^２５（式中、Ｒ^２５は、前記Ｒ^１１と同義である）、又は、Ｒ^２１とＲ^２２が一緒になって、含窒素複素環基を表す］、Ｎ（Ｒ^２６）Ｃ（＝Ｑ^２）ＮＲ^２７Ｒ^２８［式中、Ｑ^２は、酸素原子、硫黄原子、ＮＲ^２９（式中、Ｒ^２９は、前記Ｒ^１１と同義である）、ＮＣＮ、ＣＨＮＯ_２又はＣ（ＣＮ）_２を表し、Ｒ^２６は、前記Ｒ^１１と同義であり、Ｒ^２７及びＲ^２８は、同一又は異なって、それぞれ前記Ｒ^１３及びＲ^１４と同義である］、Ｎ（Ｒ^３０）ＳＯ_２ＮＲ^３１Ｒ^３２（式中、Ｒ^３０は、前記Ｒ^１１と同義であり、Ｒ^３１及びＲ^３２は、同一又は異なって、それぞれ前記Ｒ^１３及びＲ^１４と同義である）、ＳｉＲ^３３Ｒ^３４Ｒ^３５（式中、Ｒ^３３、Ｒ^３４及びＲ^３５は、同一又は異なって、前記Ｒ^１１と同義である）、ニトロ基、シアノ基又はハロゲン原子を表し、
Ｒ^２及びＲ^３は、一方の基が、

（式中、Ａｒは、置換若しくは非置換アリール基又は置換若しくは非置換芳香族複素環基を表し、Ｒ^４は、水素原子、置換若しくは非置換アルキル基、置換若しくは非置換シクロアルキル基、置換若しくは非置換アルケニル基、置換若しくは非置換アルキニル基、置換若しくは非置換脂環式複素環基、置換若しくは非置換脂環式複素環アルキル基、置換若しくは非置換アリール基、置換若しくは非置換アラルキル基、置換若しくは非置換芳香族複素環基、置換若しくは非置換芳香族複素環アルキル基を表す）
を表し、他方の基は、前記Ｒ^１と同義であり、
ｍは、０〜４の整数を表す｝
で表わされるキナゾリン化合物又はその薬理学的に許容される塩を有効成分として含有する医薬組成物に関する。 That is, the present invention
(1) Formula (I)

{Where,
R ¹ is the same or different and is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic ring Group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, COR ¹¹ wherein R ¹¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic ring Group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted Represents an unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic alkyl group), COOR ¹² (wherein R ¹² is as defined above for R ¹¹ ), C (= Q ¹ ) NR ¹³ R ¹⁴ [wherein, Q ¹ represents an oxygen atom, a sulfur atom or NR ¹⁵ (wherein R ¹⁵ has the same meaning as R ¹¹ above), and R ¹³ and R ¹⁴ represent , Same or different, hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted Or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Aromatic heterocyclic alkyl group, ^{or, R 13} and ^{R 14} are taken together, represent a nitrogen-containing heterocyclic group], ^{OR 16 (wherein, R 16} is synonymous with the ^{R 11),} OCOR ¹⁷ (Wherein R ¹⁷ has the same meaning as R ¹¹ ), S (O) pR ¹⁸ (wherein p represents 0, 1 or 2 and R ¹⁸ has the same meaning as R ¹¹ ). , SO ₂ NR ¹⁹ R ²⁰ (wherein R ¹⁹ and R ²⁰ are the same or different and have the same meanings as R ¹³ and R ¹⁴ respectively), NR ²¹ R ²² [wherein R ²¹ and R ²² are , Same or different, hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted Or an unsubstituted alicyclic compound An aromatic ring alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl group, COR ²³ (wherein R ²³ is wherein ^{R 11} as synonymous), in COOR ^{24 (wherein, R 24,} said ^{R 11} as _synonymous), SO ^{2 R 25 (wherein, R 25} is synonymous with the ^{R 11),} or , R ²¹ and R ²² together represent a nitrogen-containing heterocyclic group], N (R ²⁶ ) C (= Q ² ) NR ²⁷ R ²⁸ [wherein Q ² represents an oxygen atom, a sulfur atom, NR ²⁹ (wherein R ²⁹ is as defined above for R ¹¹ ), NCN, CHNO ₂ or C (CN) ₂ , R ²⁶ is as defined above for R ¹¹ , and R ²⁷ and R ²⁸ are , same or different, each of the ^{R 13} and ^{14 _{synonymous], N (R 30) SO}} 2 NR 31 R 32 ( ^{wherein, R 30} has the same meaning as the ^{R 11, R 31} and ^{R 32} are the same or different, each of said ^{R 13} And R ¹⁴ ), SiR ³³ R ³⁴ R ³⁵ (wherein R ³³ , R ³⁴ and R ³⁵ are the same or different and have the same meaning as R ¹¹ ), nitro group, cyano group or halogen Represents an atom,
R ² and R ^{3 each} have one group

(In the formula, Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or Unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted Or represents an unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl group)
And the other group has the same meaning as R ¹ ,
m represents an integer of 0 to 4}
And a pharmacologically acceptable salt thereof as an active ingredient.

（式中、Ｒ^１、Ｒ^２、Ｒ^４、Ａｒ及びｍは、前記と同義である）
で表わされるキナゾリン化合物であることを特徴とする上記（１）記載の医薬組成物や、
（３） Ａｒが置換フェニル基を、Ｒ^４がメチル基であることを特徴とする上記（２）記載の医薬組成物や、
（４） 置換フェニル基の置換基が、アルコキシ基又はアルキルチオ基であるであることを特徴とする上記（３）の医薬組成物や、
（５） アルコキシ基がメトキシ基又はエトキシ基を、アルキルチオ基がメチルチオ基であることを特徴とする上記（４）記載の医薬組成物や、
（６） Ｒ^２が水素原子、置換若しくは非置換フェニル基、フリル基、トリクロロメチル基、アルコキシ基、アルキルチオ基、アリルオキシ基、ジメチルアミノ基、モルホリノ基又はクロロ基であることを特徴とする上記（２）〜（５）のいずれか記載の医薬組成物や、
（７） 置換フェニル基の置換基がクロロ基を、アルコキシ基がメトキシ基又はエトキシ基を、アルキルチオ基がメチルチオ基であることを特徴とする上記（６）記載の医薬組成物や、
（８） Ｒ^１及びＲ^２が水素原子を、Ｒ^４がメチル基を、Ａｒが４−メトキシフェニル基であることを特徴とする上記（２）記載の医薬組成物や、
（９） 式（Ｉ）で表わされる化合物が下記式（Ｉｂ）

（式中、Ｒ^１、Ｒ^３、Ｒ^４、Ａｒ及びｍは、前記と同義である）
で表わされるキナゾリン化合物であることを特徴とする上記（１）記載の医薬組成物に関する。 The present invention also provides:
(2) The compound represented by the formula (I) is represented by the following formula (Ia)

(Wherein R ¹ , R ² , R ⁴ , Ar and m are as defined above)
A pharmaceutical composition according to the above (1), which is a quinazoline compound represented by:
(3) The pharmaceutical composition according to the above (2), wherein Ar is a substituted phenyl group, and R ⁴ is a methyl group,
(4) The pharmaceutical composition of (3) above, wherein the substituent of the substituted phenyl group is an alkoxy group or an alkylthio group,
(5) The pharmaceutical composition according to the above (4), wherein the alkoxy group is a methoxy group or an ethoxy group, and the alkylthio group is a methylthio group,
(6) The above, wherein R ² is a hydrogen atom, a substituted or unsubstituted phenyl group, a furyl group, a trichloromethyl group, an alkoxy group, an alkylthio group, an allyloxy group, a dimethylamino group, a morpholino group or a chloro group ( 2) to the pharmaceutical composition according to any one of (5),
(7) The pharmaceutical composition according to the above (6), wherein the substituent of the substituted phenyl group is a chloro group, the alkoxy group is a methoxy group or an ethoxy group, and the alkylthio group is a methylthio group,
(8) The pharmaceutical composition according to the above (2), wherein R ¹ and R ² are hydrogen atoms, R ⁴ is a methyl group, and Ar is a 4-methoxyphenyl group,
(9) The compound represented by the formula (I) is represented by the following formula (Ib)

(Wherein R ¹ , R ³ , R ⁴ , Ar and m are as defined above)
It is related with the pharmaceutical composition of the said (1) description characterized by the above-mentioned.

Furthermore, the present invention provides
(10) A cell growth inhibitor containing, as an active ingredient, the quinazoline compound represented by the formula (I) according to any one of (1) to (9) or a pharmacologically acceptable salt thereof,
(11) The cell growth inhibitor according to (10), wherein the cell is a cancer cell.

  The pharmaceutical composition containing the quinazoline compound of the present invention or a pharmacologically acceptable salt thereof has excellent growth inhibitory activity against cancer cells and the like.

  Specific examples of the definition of each group in the compound (I) used as the pharmaceutical composition of the present invention are shown below, but these are preferable examples of the present invention, and are of course limited by these. is not.

  The alkyl part in the alkyl group and the alkoxy group and the alkylthio group is, for example, linear or branched alkyl having 1 to 12 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Examples include tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.

  The cycloalkyl group is a 3- to 12-membered cycloalkyl group in which a saturated or partially unsaturated bond may exist, and a monocyclic or a plurality of the monocyclic cycloalkyl groups or an aryl group or an aromatic heterocycle. A polycyclic fused cycloalkyl group condensed with a cyclic group may be used. Examples of the monocyclic cycloalkyl group include monocyclic cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl. , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 1-cyclohexenyl and the like. Examples of the polycyclic cycloalkyl group include polycyclic cycloalkyl having 5 to 12 carbon atoms, specifically Specifically, pinanyl, adamantyl, bicyclo [3.3.1] octyl, bicyclo [3.1.1] heptyl and the like can be mentioned.

  The alkenyl group is, for example, linear or branched alkenyl having 2 to 12 carbon atoms, specifically vinyl, allyl, 1-propenyl, isopropenyl, methacryl, butenyl, 1,3-butadienyl, crotyl, pentenyl, Hexenyl, heptenyl, decenyl, dodecenyl and the like can be mentioned.

  The alkynyl group is, for example, linear or branched alkynyl having 2 to 12 carbon atoms, specifically ethynyl, propargyl, 1-propynyl, isopropynyl, 2-butynyl, pentynyl, 2-penten-4-ynyl, Hexinyl, heptynyl, decynyl, dodecynyl and the like can be mentioned.

  The alicyclic heterocyclic group is the same or different and contains at least one or more hetero atoms such as nitrogen, oxygen, sulfur and the like, and may have a saturated or partially unsaturated bond. An alicyclic heterocyclic group, which may be monocyclic or a polycyclic condensed alicyclic heterocyclic group in which the monocyclic heterocyclic group is condensed with an aryl group or an aromatic heterocyclic group. Good. Specific examples of monocyclic alicyclic heterocyclic groups include aziridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dihydrothiazolyl, tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, oxazolidyl, thiazolidinyl, piperidino , Piperidyl, piperazinyl, homopiperidinyl, morpholino, morpholinyl, thiomorpholinyl, pyranyl, oxathianyl, oxadiazinyl, thiadiazinyl, dithiazinyl, azepinyl, dihydroazosinyl, and the like. , Indolinyl, isoindolinyl, chromanyl, isochromanyl, quinuclidinyl, and the like.

  In the alicyclic heterocyclic alkyl group, the alicyclic heterocyclic portion has the same meaning as the alicyclic heterocyclic group, the alkyl portion has the same meaning as the alkyl group, and includes, for example, at least one or more hetero atoms. Examples of the alicyclic heterocyclic alkyl include pyrrolidinylethyl, piperidinoethyl, morpholinoethyl, and the like.

  Examples of the aryl group include aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl, phenanthryl and the like.

  The aralkyl group has the same aryl part as the aryl group, and the alkyl part has the same meaning as the alkyl group. For example, aralkyl having 7 to 15 carbon atoms, specifically benzyl, phenethyl, phenylpropyl, phenylbutyl. Benzhydryl, trityl, naphthylmethyl, naphthylethyl, phenylcyclopropyl and the like.

  The aromatic heterocyclic group is the same or different and consists of a 5-membered or 6-membered aromatic heterocyclic group containing at least one or more hetero atoms such as nitrogen, oxygen, sulfur and the like. It may be a monocyclic or a polycyclic fused aromatic heterocyclic group in which a plurality of the monocyclic heterocyclic groups are condensed with an aryl group, for example, a bicyclic or tricyclic heterocyclic group. Specific examples of the monocyclic aromatic heterocyclic group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl Examples of the polycyclic fused aromatic heterocyclic group include benzofuryl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, carbazolyl, purinyl, quinolyl, isoquinolyl Quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, pteridinyl, acridin , It may be mentioned thianthrenyl, phenoxathiinyl, cycloalkenyl, phenoxazinyl, phenothiazinyl, and phenazinyl like.

  The aromatic heterocyclic alkyl group has the same aromatic heterocyclic moiety as the aromatic heterocyclic group, and the alkyl moiety has the same meaning as the alkyl group, for example, an aromatic group containing at least one hetero atom. Heterocyclic alkyl, specifically pyridylmethyl, pyridylethyl, furanylmethyl, thienylmethyl and the like can be mentioned.

  The nitrogen-containing heterocyclic group is a heterocyclic group containing at least one nitrogen atom as a hetero atom among the alicyclic heterocyclic group or the aromatic heterocyclic group, specifically, aziridinyl, pyrrolidinyl, Examples include piperidino, homopiperidinyl, piperazinyl, homopiperazinyl, morpholino, thiomorpholinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl and the like.

  The halogen atom means each atom of fluorine, chlorine, bromine and iodine.

  In addition, groups in which regioisomers exist in each of these groups represent all possible regioisomers.

Alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alicyclic heterocyclic group, alicyclic heterocyclic alkyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group and nitrogen-containing heterocyclic group Examples of the substituent in the cyclic group include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an alicyclic heterocyclic group, an alicyclic heterocyclic alkyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, and an aromatic group. Heterocyclic alkyl group, OR ^a , NR ^b R ^c , S (O) tR ^d (where t represents 0, 1 or 2), COR ^e , COOR ^f , OCOR ^g , CONR ^h R ⁱ , NR ^{j COR k, NR l COOR m} , NR n SO 2 R o, C (= NR p) NR q R r, NR s SO 2 NR t R u, SO 2 NR v R w, nitro group, cyano group, halo Emissions atom is suitably selected from oxo group and thioxo group. Here, R ^{a to} R ^w are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an alicyclic heterocyclic group, an alicyclic heterocyclic alkyl group, an aryl group, or an aralkyl. A group, an aromatic heterocyclic group, an aromatic heterocyclic alkyl group, etc., R ^b and R ^c , R ^h and R ⁱ , R ^q and R ^r , R ^t and R ^u and R ^v and R ^w are To form a nitrogen-containing heterocyclic group.

  Alkyl group, alkenyl group, alkynyl group, cycloalkyl group, alicyclic heterocyclic group, alicyclic heterocyclic alkyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group and nitrogen-containing heterocyclic group The cyclic group has the same meaning as described above.

  In addition, as a substituent, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an alicyclic heterocyclic group, an alicyclic heterocyclic alkyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, an aromatic heterocyclic ring The alkyl group and the nitrogen-containing heterocyclic group may further have a substituent, and examples of the substituent include the same as those described above.

  The number of substitution of these substituents may be the same or different and may be up to the number of hydrogen atoms present in each group, but is preferably 1 to 10, more preferably 1 to 5.

  Examples of the pharmacologically acceptable salt of the compound represented by the formula (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. . Pharmacologically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, and formic acid, acetic acid, propionic acid and fumaric acid as organic acids. Examples thereof include carboxylic acids such as acid, malonic acid, succinic acid, maleic acid, tartaric acid, citric acid and benzoic acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid. Examples of pharmacologically acceptable metal salts include alkali metal salts such as lithium, sodium and potassium, alkaline earth metal salts such as magnesium and calcium, and metal salts such as aluminum and zinc. Acceptable ammonium salts include ammonium and tetramethylammonium salts, and pharmacologically acceptable organic amine salts include triethylamine, piperidine, morpholine, toluidine and other pharmacologically acceptable salts. Examples of amino acid addition salts include addition salts of lysine, glycine, phenylalanine and the like.

  Next, the manufacturing method of compound (I) is demonstrated.

Manufacturing method 1
Compound (I) can be produced according to the following reaction step according to the method described in Non-Patent Document 1.

[Wherein, L ¹ represents a halogen atom, L ² represents MgX (wherein X represents a halogen atom), a halogen atom or a tetramethylsilyl group, and R ¹ , R ² , R ⁴ , Ar And m are as defined above.]
Here, the halogen atom has the same meaning as described above.

(Process 1)
4-Aroylquinazoline compound (IVa) obtained by aroylating the 4-position of quinazoline is obtained by converting 4-halogenated quinazoline compound (IIa) and aldehyde compound (III) into 1,3-dimethylimidazolium iodide, iodide 1 It can be obtained by reacting in the presence of a base such as sodium hydride using a nitrogen-containing heterocyclic carbene such as-(2-ethoxyethyl) -3-methylimidazolium as a catalyst.

(Process 2)
The target compound (Ia) having a hydroxymethyl group at the 4-position can be obtained by reacting compound (IVa) with compound (V) such as a Grignard reagent.

(Process 3)
2,4-diaroylquinazoline compound (IVb) having an aroyl group at the 2-position and 4-position of quinazoline is obtained by adding 2 equivalents or more of compound (III) to compound (IIa) wherein R ² is a halogen atom (L ¹ ). It can be obtained by reacting according to the method of Step 1.

(Process 4)
Compound (IVb) can also be obtained according to the method of Step 1 from Compound (IVa) in which R ² obtained in Step 1 is a halogen atom (L ¹ ).

(Process 5)
Compound (Ic) in which both the 2-position and 4-position of quinazoline are hydroxymethyl groups can be obtained by reacting compound (IVb) with 2 equivalents or more of compound (V) according to the method of Step 2.

(Step 6)
The target compound (Ib) in which the 2-position is a hydroxymethyl group and R ³ is a hydrogen atom can be obtained by allowing a cyanide ion such as potassium cyanide or tetrabutylammonium cyanide to act on the compound (Ic).
Manufacturing method 2

(Wherein R ¹ , R ³ , R ⁴ , Ar, L ¹ , L ² and m are as defined above)

(Step 7)
The 2-aroylquinazoline compound (IVc) obtained by aroylating the 2-position of quinazoline can be obtained from the 2-halogenated quinazoline compound (IIb) and the aldehyde compound (III) according to the method of Step 1.

(Process 8)
The target compound (Ib) having a hydroxymethyl group at the 2-position can be obtained from the compound (IVc) according to the method of Step 2.

Production method 3
(Step 9)
In the compound (I), a compound in which R ⁴ is a hydrogen atom can be obtained by reducing the aroylquinazoline compound (IV) represented by the compound (IVa) or (IVb) or the like.

(Wherein Ar is as defined above)
Examples of the reducing agent used for the reduction include sodium borohydride.

Further, various substituents such as ^R 1, ^{R 2} and ^{R 3} in the compound (I), for example, compounds obtained by the above production method (I) or ^R 1 to R ³ are halogen atoms in the intermediates ( It can also be obtained by reacting a compound that is L ¹ ) with a nucleophile or the like.

  The reaction in each of the above steps is carried out by using a suitable inert solvent, for example, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as benzene and toluene, an ether such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. In a system solvent, an aprotic polar solvent such as N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), a basic solvent such as pyridine or quinoline, or a mixed solvent thereof, It can be obtained by reacting at a temperature between 78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours.

  In each of the above production methods, when the defined group changes under the conditions of the method of implementation or is inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in synthetic organic chemistry [eg, protective・ See Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1981)] By using it, the target compound can be obtained. Further, the functional group contained in each substituent may be converted by a known method [eg, Comprehensive Organic Transformations, R.A. C. Larock (1989), etc.], and some of the compounds (I) can be further converted into other derivatives (I) as synthetic intermediates.

  The intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Although some isomers may exist in Compound (I), the present invention can use all possible isomers and mixtures thereof as anticancer agents.

  When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, the salt may be formed by suspending and adding an acid or a base by a usual method.

  Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts may also be used as the pharmaceutical composition of the present invention. Can do.

  Specific examples of the compound (I) obtained by the above production method are shown in Tables 1 to 5.

  Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to prepare various pharmaceutical preparations. It can be produced by a conventional method of pharmaceutics by mixing with one or two or more types of carriers that are acceptable.

  Examples of the administration route include oral administration, inhalation administration and parenteral administration such as intravenous administration.

  Examples of the dosage form include tablets, injections, etc. The tablets are mixed with various additives such as lactose, starch, magnesium stearate, hydroxypropyl cellulose, polyvinyl alcohol, surfactant, glycerin, etc. The inhalant may be produced according to a conventional method by adding, for example, lactose. An injection may be produced according to a conventional method by adding water, physiological saline, vegetable oil, solubilizer, preservative and the like.

  The effective amount and frequency of administration of compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms, etc., but usually 0.001 mg to 5 g per adult, preferably Is administered in a dose of 0.1 mg to 1 g, more preferably 1 to 500 mg, once a day or several times a day.

  Hereinafter, the present invention will be described more specifically with reference to examples, production examples, and the like, but the technical scope of the present invention is not limited to these exemplifications.

A549 cell growth inhibitory activity A549 cells were seeded in a 96-well plate (Greiner) (5 × 10 ³ cells / well), phenol red-free DMEM medium (GIBCO) containing 10% FBS and 20 units / mL Penicillin / Streptomycin. ) At 37 ° C. in the presence of 5% CO ₂ overnight. A medium containing each concentration of a test compound (DMSO final concentration of 0.25%) prepared immediately before use was added and contacted at 37 ° C. in the presence of 5% CO ₂ for 72 hours.
The medium in each well was removed and the plate was washed with PBS and medium. After adding 100 μL of the medium, 20 μL of CellTiter 96 AQueous One Solution Reagent (Promega) was added. Immediately after the addition of the reaction reagent, the absorbance at 495 nm was measured using a Multiplate reader (Molecular Device). Furthermore, after reacting at 37 ° C. in the presence of 5% CO ₂ for 1 hour, the absorbance was measured, and the cell growth inhibition rate was calculated by the following formula.

Cell growth inhibition rate (%) = 100−100 × (A _s −A _b ) / (A _c −A _b )
A _s: absorbance A _c after reaction wells treated with the test _compound: DMSO treated only with absorbance A _b after the reaction _wells: absorbance after reaction reagent addition in each well

  The test result was expressed as a cell growth inhibition rate at a concentration of 25 μM of each compound. The results are shown in Table 6.

  Tablets are prepared by a conventional method using a composition comprising 10 mg of compound (Compound Ia-8), 70 mg of lactose, 15 mg of starch, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate (total 100 mg).

In a conventional manner, 70 ml of compound (Compound Ia-22), 50 mg of purified soybean oil, 10 mg of egg yolk lecithin and 25 mg of glycerin were added with distilled water for injection to a total volume of 100 mL, filled into vials, and then heat sterilized. To prepare an injection.
[Production Example 1]

1-Phenyl-1- (quinazolin-4-yl) ethanol (Compound Ia-1)
To a solution of 4-benzoylquinazoline (compound a) (117 mg, 0.5 mmol) obtained in Reference Example 1 in THF (4 mL) was added 1M diethyl ether solution (1.5 mL, 1.5 mmol) of methylmagnesium iodide under ice-cooling. The solution was added dropwise and stirred overnight at room temperature under an argon atmosphere. The reaction solution was poured into an aqueous ammonium chloride solution, and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound (70 mg, 0.28 mmol) as colorless crystals in a yield of 55%.
¹ H-NMR (CDCl ₃ ) δ: 9.35 (1H, s), 8.07 (1H, d, J = 9.1 Hz), 7.81-7.78 (1H, m), 7.73 (1H, d, J = 7.9 Hz), 7.41-7.25 (6H, m), 7.05 (0H, s), 6.38 (1H, s).
FAB-Mass: 251 ((M + 1) ⁺ )
[Production Example 2]

1- (3-Hydroxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-2)
The title compound was obtained by catalytic reduction of Compound Ia-4 obtained in Production Example 4 using palladium on carbon in a hydrogen atmosphere.
¹ H-NMR (CDCl ₃ ) δ: 9.26 (1H, s), 8.02 (1H, dd, J = 9.2 Hz, 1.2 Hz), 7.79-7.76 (2H, m), 7.42-7.38 (1H, m), 7.21 (1H, t, J = 7.5 Hz), 7.03 (1H, dd, J = 6.1 Hz, 1.2 Hz), 6.77-6.75 (2H, m), 6.28 (1H, s), 5.57 (1H, s), 2.09 (3H, s).
FAB-Mass: 255 ((M + 1) ⁺ )
[Production Example 3]

1- (3-Methoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-3)
Using the compound b obtained in Reference Example 2 instead of 4-benzoylquinazoline (Compound a), the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.06 (1H, dd, J = 9.0 Hz, 1.0 Hz), 7.81-7.78 (2H, m), 7.41-7.39 (1H, m), 7.24 (1H, d, J = 8.0 Hz), 6.97-6.92 (2H, m), 6.81 (1H, dd, J = 9.0 Hz, 2.5 Hz), 6.33 (1H, s), 3.74 (5H, s), 3.05 (0H, s), 2.10 (4H, s).
FAB-Mass: 281 ((M + 1) ⁺ )
[Production Example 4]

1- (3-Benzyloxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-4)
Using the compound c obtained in Reference Example 3 in place of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.33 (1H, s), 8.06 (1H, d, J = 8.5 Hz), 7.80 (1H, t, J = 7.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.39-7.24 (8H, m), 7.00 (1H, d, J = 8.0 Hz), 6.90-6.88 (1H, m), 6.41 (1H, s), 5.00 (2H, q, J = 11.0 Hz ), 2.09 (3H, s).
FAB-Mass: 357 ((M + 1) ⁺ )
[Production Example 5]

1- (4-Fluorophenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-5)
Using the compound d obtained in Reference Example 4 in place of the compound a, the title compound was obtained according to the method described in Production Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.08 (1H, d, J = 8.5 Hz), 7.83-7.80 (1H, m), 7.70 (1H, d, J = 8.5 Hz), 7.42-7.36 (4H, m), 7.03-6.99 (2H, m), 6.40 (1H, s), 2.12 (4H, s).
FAB-Mass: 269 ((M + 1) ⁺ )
[Production Example 6]

1- (4-Chlorophenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-6)
Using the compound e obtained in Reference Example 5 in place of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.08 (1H, d, J = 8.5 Hz), 7.84-7.80 (1H, m), 7.71 (1H, d, J = 8.5 Hz), 7.43-7.40 (1H, m), 7.33 (2H, d, J = 8.5 Hz), 7.30 (2H, d, J = 8.5 Hz), 6.34 (1H, s), 2.11 (4H, s).
FAB-Mass: 285 ((M + 1) ⁺ )
[Production Example 7]

1- (4-Trifluoromethylphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-7)
Using the compound f obtained in Reference Example 6 instead of the compound a, the title compound was obtained according to the method described in Production Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.35 (1H, s), 8.08 (1H, d, J = 8.6 Hz), 7.84-7.81 (1H, m), 7.71 (1H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.49-7.41 (1H, m), 6.36 (1H, s), 2.15 (3H, s).
FAB-Mass: 319 ((M + 1) ⁺ )
[Production Example 8]

1- (4-Methoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-8)
Using the compound g obtained in Reference Example 7 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.07 (1H, d, J = 8.5 Hz), 7.82-7.79 (1H, m), 7.75 (1H, d, J = 8.5 Hz), 7.41-7.38 (1H, m), 7.31 (2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 6.44 (1H, s), 3.79 (3H, s), 2.11 (3H , s).
FAB-Mass: 281 ((M + 1) ⁺ )

Compound Ia-8 obtained above was used with CHIRALCELL-OD (φ1.0 cm × 25 cm) (manufactured by Daicel), and hexane-isopropanol (95/5) as an eluent (elution rate: 1 mL / min). The enantiomer was resolved.
CHIRALCELL-OD (φ0.45 cm × 25 cm) (manufactured by Daicel Corporation) was used as an analytical column, and hexane-isopropanol (95/5) was analyzed as an eluent (elution rate: 1 mL / min).
(−) Body: retention time 21.7 minutes (+) body: retention time 26.8 minutes [Production Example 9]

1- (4-Ethoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-9)
The title compound was obtained according to the method described in Production Example 1 using Compound h obtained in Reference Example 8 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.33 (1H, s), 8.06 (1H, d, J = 8.6 Hz), 7.79 (1H, dt, J = 8.0 Hz, 1.0 Hz), 7.74 (1H, d, J = 8.0 Hz), 7.39 (1H, t, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 6.50 (1H, s), 4.00 (2H, q, J = 7.0 Hz), 2.10 (3H, s), 1.39 (3H, t, J = 7.0 Hz).
FAB-Mass: 295 ((M + 1) ⁺ )
[Production Example 10]

1- (4-n-Butoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-10)
The title compound was obtained according to the method described in Preparation Example 1, using Compound i obtained in Reference Example 9 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.32 (1H, s), 8.05 (1H, d, J = 8.5 Hz), 7.80-7.76 (2H, m), 7.38 (1H, dt, J = 11.1 Hz, 3.8 Hz), 7.29 (2H, d, J = 8.5 Hz), 6.83 (2H, d, J = 8.5 Hz), 6.46 (1H, s), 3.92 (2H, t, J = 6.5 Hz), 2.09 (3H, s), 1.76-1.70 (2H, m), 1.48-1.44 (2H, m), 0.95 (3H, t, J = 7.5 Hz).
FAB-Mass: 323 ((M + 1) ⁺ )
[Production Example 11]

1- (4-Trifluoromethoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-11)
The title compound was obtained according to the method described in Preparation Example 1, using Compound j obtained in Reference Example 10 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.35 (1H, s), 8.09 (1H, d, J = 8.5 Hz), 7.84-7.81 (1H, m), 7.71 (1H, d, J = 8.5 Hz), 7.44-7.40 (3H, m), 7.17 (2H, d, J = 8.5 Hz), 6.35 (1H, s), 2.13 (4H, s).
FAB-Mass: 335 ((M + 1) ⁺ )
[Production Example 12]

1- (4-Methylthiophenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-12)
The title compound was obtained according to the method described in Preparation Example 1, using Compound k obtained in Reference Example 11 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.09 (1H, d, J = 8.5 Hz), 7.82-7.79 (1H, m), 7.74 (1H, d, J = 8.5 Hz), 7.40 (1H, ddd, J = 8.5 Hz, 7.0 Hz, 1.0 Hz), 7.30 (2H, d, J = 8.5 Hz), 7.20 (2H, d, J = 8.5 Hz), 6.40 (1H, s), 2.45 (4H, s), 2.10 (3H, s).
FAB-Mass: 297 ((M + 1) ⁺ )
[Production Example 13]

1- (4-Methylaminophenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-13)
The title compound was obtained according to the method described in Production Example 1 using Compound 1 obtained in Reference Example 12 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.31 (1H, s), 8.05 (1H, d, J = 8.0 Hz), 7.82-7.77 (2H, m), 7.38 (1H, ddd, J = 8.5 Hz, 8.0 Hz, 1.0 Hz), 7.18 (2H, d, J = 8.5 Hz), 6.54 (2H, d, J = 8.5 Hz), 6.46 (1H, s), 2.81 (3H, s), 2.07 (3H, s) .
FAB-Mass: 280 ((M + 1) ⁺ )
[Production Example 14]

1- (4-Dimethylaminophenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-14)
Using the compound m obtained in Reference Example 13 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.32 (1H, s), 8.05 (1H, d, J = 8.0 Hz), 7.82-7.76 (2H, m), 7.40-7.37 (1H, ddd, J = 8.5 Hz , 8.0 Hz, 1.0 Hz), 7.22 (2H, d, J = 8.5 Hz), 6.66 (2H, d, J = 8.5 Hz), 6.39 (1H, s), 2.92 (8H, s), 2.08 (4H, s).
FAB-Mass: 294 ((M + 1) ⁺ )
[Production Example 15]

1- (3,4-Methylenedioxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-15)
Using the compound n obtained in Reference Example 14 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.32 (1H, s), 8.07 (1H, dd, J = 9.0 Hz, 1.0 Hz), 7.83-7.80 (2H, m), 7.42 (1H, td, J = 8.0 Hz, 1.5 Hz), 6.95 (1H, dd, J = 8.0 Hz, 2.0 Hz), 6.78-6.76 (2H, m), 6.41 (1H, s), 5.92 (1H, d, J = 11.5 Hz), 5.92 (1H, d, J = 11.5 Hz), 2.07 (4H, s).
FAB-Mass: 295 ((M + 1) ⁺ )
[Production Example 16]

1- (3,4-Dimethoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-16)
Using the compound o obtained in Reference Example 15 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.07 (1H, d, J = 8.5 Hz), 7.83-7.77 (2H, m), 7.41-7.38 (1H, m), 7.01 (1H , dd, J = 8.2 Hz, 2.1 Hz), 6.84-6.82 (2H, m), 6.41 (1H, s), 3.86 (4H, s), 3.74 (4H, s), 2.10 (3H, s).
FAB-Mass: 311 ((M + 1) ⁺ )
[Production Example 17]

1- (3,4,5-Trimethoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-17)
The title compound was obtained according to the method described in Preparation Example 1, using Compound p obtained in Reference Example 16 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 9.34 (1H, s), 8.08 (1H, d, J = 8.0 Hz), 7.85-7.80 (2H, m), 7.45-7.42 (1H, m), 6.60 (2H , s), 6.29 (1H, s), 3.82 (3H, s), 3.76 (6H, s), 2.09 (3H, s).
FAB-Mass: 341 ((M + 1) ⁺ )
[Production Example 18]

(4-Methoxyphenyl) (quinazolin-4-yl) methanol (Compound Ia-18)
The title compound was obtained by reducing compound g obtained in Reference Example 7 with sodium borohydride.
¹ H-NMR (CDCl ₃ ) δ: 9.44 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8.07 (2H, t, J = 8.0 Hz), 8.01-7.95 (3H, m), 7.68 (1H, t, J = 7.5 Hz), 6.99 (2H, d, J = 9.0 Hz), 6.97 (1H, d, J = 7.5 Hz), 3.91 (3H, s), 3.91 (2H, d, J = 7.5 Hz).
FAB-Mass: 267 ((M + 1) ⁺ )
[Production Example 19]

1- (4-Methoxyphenyl) -1- (quinazolin-4-yl) propan-4-ol (Compound Ia-19)
The title compound was obtained according to the method described in Production Example 1, except that Compound g obtained in Reference Example 7 was used instead of Compound a and ethylmagnesium iodide was used instead of methylmagnesium iodide.
¹ H-NMR (CDCl ₃ ) δ: 9.33 (1H, s), 8.06 (1H, d, J = 7.5 Hz), 7.82-7.78 (2H, m), 7.40 (1H, td, J = 7.5 Hz, 1.0 Hz), 7.31 (2H, d, J = 8.5 Hz), 6.84 (2H, d, J = 8.5 Hz), 6.45 (1H, s), 3.77 (3H, s), 2.70 (2H, td, J = 14.5 Hz, 7.5 Hz), 2.62 (2H, td, J = 14.5 Hz, 7.5 Hz), 0.64 (3H, t, J = 7.5 Hz).
FAB-Mass: 295 ((M + 1) ⁺ )
[Production Example 20]

2,2,2-trifluoro-1- (4-methoxyphenyl) -1- (quinazolin-4-yl) ethanol (Compound Ia-20)
To a THF (4 mL) solution of the compound g (132 mg, 0.5 mmol) obtained in Reference Example 7 was added 1M THF solution (20 μL, trifluoromethyltrimethylsilane (177 μL, 1.2 mmol) and tetrabutylammonium fluoride under ice-cooling. 0.02 mmol) was added, and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction mixture was poured into water and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound (95 mg, 0.28 mmol) as colorless crystals in a yield of 57%.
¹ H-NMR (CDCl ₃ ) δ: 9.41 (1H, s), 8.10 (1H, d, J = 8.5 Hz), 7.83 (1H, ddd, J = 8.0 Hz, 7.3 Hz, 1.2 Hz), 7.69 (1H , d, J = 9.1 Hz), 7.41-7.34 (3H, m), 7.13 (1H, s), 6.88 (2H, d, J = 9.1 Hz), 3.80 (3H, s).
FAB-Mass: 335 ((M + 1) ⁺ )
[Production Example 21]

1- (4-Methoxyphenyl) -2-phenyl-1- (quinazolin-4-yl) ethanol (Compound Ia-21)
The title compound was obtained according to the method described in Preparation Example 1, except that Compound g obtained in Reference Example 7 was used in place of Compound a instead of methylmagnesium iodide and phenylmagnesium bromide was used.
¹ H-NMR (CDCl ₃ ) δ: 9.06 (1H, s), 8.07 (1H, d, J = 8.0 Hz), 7.99 (1H, d, J = 8.5 Hz), 7.87-7.83 (1H, m), 7.49 (1H, t, J = 8.0 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.08 (1H, t, J = 8.0 Hz), 7.00 (2H, t, J = 8.0 Hz), 6.90 ( 2H, d, J = 9.0 Hz), 6.65 (2H, d, J = 8.0 Hz), 5.95 (1H, s), 3.97 (1H, d, J = 13.0 Hz), 3.93 (1H, d, J = 13.0 Hz), 3.82 (3H, s).
FAB-Mass: 357 ((M + 1) ⁺ )
[Production Example 22]

1- (4-Methoxyphenyl) -1- (2-methylquinazolin-4-yl) ethanol (Compound Ia-22)
Using the compound q obtained in Reference Example 17 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.97 (1H, d, J = 8.5 Hz), 7.77-7.73 (1H, m), 7.64 (1H, d, J = 8.5 Hz), 7.33-7.29 (3H, m ), 6.86 (2H, d, J = 8.5 Hz), 6.85 (1H, s), 3.79 (3H, s), 2.98 (3H, s), 2.09 (3H, s).
FAB-Mass: 295 ((M + 1) ⁺ )
[Production Example 23]

1- (4-Methoxyphenyl) -1- (2-phenylquinazolin-4-yl) ethanol (Compound Ia-23)
The title compound was obtained according to the method described in Production Example 1 using Compound r obtained in Reference Example 18 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 8.68 (2H, dd, J = 8.0 Hz, 2.0 Hz), 8.10 (1H, d, J = 8.0 Hz), 7.78-7.72 (2H, m), 7.60-7.53 ( 3H, m), 7.38-7.31 (3H, m), 6.85 (2H, d, J = 8.5 Hz), 6.69 (1H, s), 3.78 (3H, s), 2.15 (3H, s).
FAB-Mass: 357 ((M + 1) ⁺ )
[Production Example 24]

1- (4-Methoxyphenyl) -1- (2-trichloromethylquinazolin-4-yl) ethanol (Compound Ia-24)
The title compound was obtained according to the method described in Production Example 1 using Compound s obtained in Reference Example 19 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 7.98 (1H, d, J = 9.0 Hz), 7.82-7.79 (2H, m), 7.40-7.37 (1H, m), 7.32 (2H, d, J = 8.5 Hz ), 6.86 (2H, d, J = 8.5 Hz), 5.53 (1H, s), 3.78 (3H, s), 2.10 (3H, s).
FAB-Mass: 397 ((M + 1) ⁺ )
[Production Example 25]

1- (4-Methoxyphenyl) -1- (2-chloroquinazolin-4-yl) ethanol (Compound Ia-25)
The title compound was obtained according to the method described in Production Example 1 using Compound t obtained in Reference Example 20 instead of Compound a.
¹ H-NMR (CDCl ₃ ) δ: 7.96 (1H, d, J = 8.5 Hz), 7.83-7.78 (2H, m), 7.41-7.36 (1H, m), 7.31 (2H, d, J = 8.5 Hz ), 6.85 (3H, d, J = 8.5 Hz), 5.58 (1H, s), 3.77 (4H, s), 2.09 (3H, s).
FAB-Mass: 315 ((M + 1) ⁺ )
[Production Example 26]

1- [2- (2-Chlorophenyl) quinazolin-4-yl] -1- (4-methoxyphenyl) ethanol (Compound Ia-26)
Compound Ia-25 obtained in Production Example 25 (31 mg, 0.1 mmol), 2-chlorophenylboronic acid (25 mg, 0.15 mmol), potassium carbonate (28 mg, 0.2 mg), palladium acetate (1.2 mg, 0. 005 mol), 1,1′-di-tert-butylphosphinoferrocene (Dt-BPF) (2.4 mg, 0.005 mol) in 1,4-dioxane (5 mL) was refluxed under an argon atmosphere for 20 hours. . The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (42 mg, 0.15 mmol) as colorless crystals in a yield of 90%.
¹ H -NMR (CDCl ₃ ) δ: 8.13 (1H, d, J = 8.5 Hz), 8.04-8.02 (1H, m), 7.73-7.76 (2H, m), 7.60-7.58 (1H, m), 7.48 -7.44 (2H, m), 7.42-7.37 (3H, m), 6.87 (2H, d, J = 9.1 Hz), 6.73 (1H, s), 3.78 (3H, s), 2.17 (2/5 x 3H , s), 2.15 (3/5 x 3H, s).
FAB-Mass: 391 ((M + 1) ⁺ )
[Production Example 27]

1- [2- (3-Chlorophenyl) quinazolin-4-yl] -1- (4-methoxyphenyl) ethanol (Compound Ia-27)
The title compound was obtained according to the method described in Production Example 26 using 3-chlorophenylboronic acid instead of 2-chlorophenylboronic acid.
¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, t, J = 2.0 Hz), 8.58-8.55 (1H, m), 8.10 (1H, d, J = 8.0 Hz), 7.80-7.74 (2H, m ), 7.54-7.51 (2H, m), 7.37-7.34 (3H, m), 6.86 (2H, d, J = 9.0 Hz), 6.53 (1H, s), 3.78 (3H, s), 2.16 (3H, s).
FAB-Mass: 391 ((M + 1) ⁺ )
[Production Example 28]

1- [2- (4-Chlorophenyl) quinazolin-4-yl] -1- (4-methoxyphenyl) ethanol (Compound Ia-28)
The title compound was obtained according to the method described in Production Example 26 using 4-chlorophenylboronic acid instead of 2-chlorophenylboronic acid.
¹ H-NMR (CDCl ₃ ) δ: 8.63 (2H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.0 Hz), 7.80-7.76 (1H, m), 7.73 (1H, d, J = 8.0 Hz), 7.55 (2H, d, J = 8.5 Hz), 7.37-7.27 (3H, m), 6.86 (2H, d, J = 9.0 Hz), 6.53 (1H, s), 3.78 (3H, s ), 2.15 (3H, s).
FAB-Mass: 391 ((M + 1) ⁺ )
[Production Example 29]

1- (4-Methoxyphenyl) -1- (3-thienylquinazolin-4-yl) ethanol (Compound Ia-29)
The title compound was obtained according to the method described in Production Example 26 using 3-thienylboronic acid in place of 2-chlorophenylboronic acid.
¹ H-NMR (CDCl ₃ ) δ: 8.50 (1H, dd, J = 3.5 Hz, 1.0 Hz), 8.11 (1H, dd, J = 5.0 Hz, 1.0 Hz), 8.04 (1H, d, J = 8.0 Hz ), 7.77-7.73 (1H, m), 7.68 (1H, d, J = 8.5 Hz), 7.47 (1H, dd, J = 5.0 Hz, 3.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.32-7.28 (1H, m), 6.85 (2H, d, J = 8.5 Hz), 6.67 (1H, s), 3.78 (4H, s), 2.14 (3H, s).
FAB-Mass: 263 ((M + 1) ⁺ )
[Production Example 30]

4- [1-Hydroxy-1- (4-methoxyphenyl) ethyl] quinazolin-2 (1H) -one (Compound Ia-30)
The title compound was obtained by hydrolyzing compound Ia-25 obtained in Production Example 25 with an aqueous sodium hydroxide solution.
¹ H-NMR (CDCl ₃ ) δ: 12.28 (1H, s), 7.61 (1H, t, J = 8.5 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.49 (1H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz), 7.03 (1H, t, J = 8.5 Hz), 6.88 (2H, d, J = 8.5 Hz), 6.02 (1H, s), 3.79 (3H, s), 2.09 (3H, s).
FAB-Mass: 297 ((M + 1) ⁺ )
[Production Example 31]

1- (4-Methoxyphenyl) -1- (2-methoxyquinazolin-4-yl) ethanol (Compound Ia-31)
The title compound was obtained by reacting Compound Ia-25 obtained in Production Example 25 with a 1M methanol solution of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.83 (1H, d, J = 8.5 Hz), 7.70-7.65 (2H, m), 7.33 (2H, d, J = 8.5 Hz), 7.19-7.15 (1H, m ), 6.85 (2H, d, J = 8.5 Hz), 5.96 (1H, s), 4.21 (3H, s), 3.79 (3H, s), 2.10 (3H, s).
FAB-Mass: 311 ((M + 1) ⁺ )
[Production Example 32]

1- (2-Ethoxyquinazolin-4-yl) -1- (4-methoxyphenyl) ethanol (Compound Ia-32)
The title compound was obtained according to the method described in Preparation Example 31 using sodium ethoxide instead of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, d, J = 8.5 Hz), 7.68-7.62 (2H, m), 7.32 (2H, d, J = 9.0 Hz), 7.17-7.13 (1H, m ), 6.84 (2H, d, J = 9.0 Hz), 6.02 (1H, s), 4.64 (2H, q, J = 7.0 Hz), 3.78 (3H, s), 2.08 (3H, s), 1.56 (9H , t, J = 7.0 Hz).
FAB-Mass: 321 ((M + 1) ⁺ )
[Production Example 33]

1- (4-Methoxyphenyl) -1- (2-propoxyquinazolin-4-yl) ethanol (Compound Ia-33)
The title compound was obtained according to the method described in Preparation Example 31 using sodium propoxide instead of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.80 (1H, d, J = 8.0 Hz), 7.68-7.64 (1H, m), 7.62 (1H, d, J = 8.0 Hz), 7.32 (2H, d, J = 9.0 Hz), 7.16-7.13 (1H, m), 6.84 (2H, d, J = 9.0 Hz), 6.09 (1H, s), 4.55-4.51 (2H, m), 3.78 (3H, s), 2.08 (3H, s), 1.97 (2H, sextet, J = 7.5 Hz), 1.13 (3H, t, J = 7.5 Hz).
FAB-Mass: 335 ((M + 1) ⁺ )
[Production Example 34]

1- (2-Allyloxyquinazolin-4-yl) -1- (4-methoxyphenyl) ethanol (Compound Ia-34)
The title compound was obtained according to the method described in Production Example 31 using sodium allyloxide instead of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 8.5 Hz), 7.68-7.63 (2H, m), 7.32 (2H, d, J = 9.0 Hz), 7.18-7.15 (1H, m ), 6.84 (2H, d, J = 9.0 Hz), 6.27-6.19 (1H, m), 6.01 (1H, s), 5.54 (1H, dq, J = 17.1 Hz, 1.5 Hz), 5.37 (1H, dd , J = 10.5 Hz, 1.5 Hz), 5.10 (2H, dt, J = 5.5 Hz, 1.0 Hz), 3.78 (3H, s), 2.08 (3H, s).
FAB-Mass: 333 ((M + 1) ⁺ )
[Production Example 35]

1- (4-Methoxyphenyl) -1- (2-phenoxyquinazolin-4-yl) ethanol (Compound Ia-35)
The title compound was obtained according to the method described in Preparation Example 31 using sodium phenoxide instead of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.79 (1H, d, J = 8.5 Hz), 7.70-7.66 (2H, m), 7.48 (2H, dd, J = 8.5 Hz, 7.5 Hz), 7.36-7.28 ( 4H, m), 7.23-7.19 (1H, m), 6.86 (2H, d, J = 9.0 Hz), 5.77 (1H, s), 3.79 (3H, s), 2.08 (3H, s).
FAB-Mass: 372 ((M + 1) ⁺ )
[Production Example 36]

1- (4-Methoxyphenyl) -1- (2-methylthioquinazolin-4-yl) ethanol (Compound Ia-36)
The title compound was obtained according to the method described in Preparation 31 using 15% sodium methanethiolate solution instead of sodium methoxide.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, d, J = 8.0 Hz), 7.71-7.67 (1H, m), 7.61 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.23-7.20 (1H, m), 6.85 (2H, d, J = 8.5 Hz), 6.21 (1H, s), 3.78 (3H, s), 2.74 (3H, s), 2.17 (2H , s), 2.08 (3H, s).
FAB-Mass: 323 ((M + 1) ⁺ )
[Production Example 37]

1- (2-Dimethylaminoquinazolin-4-yl) -1- (4-methoxyphenyl) ethanol (Compound Ia-37)
Using dimethylamine instead of piperidine, the title compound was obtained according to the method described in Production Example 39.
¹ H-NMR (CDCl ₃ ) δ: 7.59 (1H, d, J = 8.5 Hz), 7.52-7.48 (1H, m), 7.39 (1H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5 Hz), 6.91-6.87 (1H, m), 6.84 (2H, d, J = 8.5 Hz), 6.60 (1H, s), 3.78 (3H, s), 3.38 (6H, s), 2.05 (3H , s).
FAB-Mass: 320 ((M + 1) ⁺ )
[Production Example 38]

1- (4-Methoxyphenyl) -1- (2-phenylaminoquinazolin-4-yl) ethanol (Compound Ia-38)
Using aniline in place of piperidine, the title compound was obtained according to the method described in Preparation Example 39.
¹ H-NMR (CDCl ₃ ) δ: 7.82 (2H, d, J = 8.0 Hz), 7.76 (1H, d, J = 8.0 Hz), 7.62-7.55 (2H, m), 7.51 (1H, d, J = 8.5 Hz), 7.41-7.34 (4H, m), 7.11-7.03 (2H, m), 6.86 (2H, d, J = 9.0 Hz), 6.25 (1H, s), 3.78 (3H, s), 2.10 (3H, s).
FAB-Mass: 373 ((M + 1) ⁺ )
[Production Example 39]

1- (4-Methoxyphenyl) -1- (2-piperidinoquinazolin-4-yl) ethanol (Compound Ia-39)
A solution of compound Ia-25 (62 mg, 0.2 mmol) and piperidine (34 mg, 0.4 mmol) in 1,4-dioxane (5 mL) was refluxed for 3 hours. After cooling, the reaction solution was poured into water, and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound (53 mg, 0.15 mmol) as yellow crystals in a yield of 74%.
¹ H-NMR (CDCl ₃ ) δ: 7.56 (1H, d, J = 7.9 Hz), 7.51-7.48 (1H, m), 7.38 (1H, d, J = 8.5 Hz), 7.33 (2H, d, J = 9.2 Hz), 6.89 (1H, ddd, J = 8.5 Hz, 6.9 Hz, 1.7 Hz), 6.85 (2H, d, J = 9.2 Hz), 6.52 (1H, s), 4.00-3.98 (4H, m) , 3.79 (3H, s), 2.06 (3H, s), 1.77-1.70 (6H, m).
FAB-Mass: 364 ((M + 1) ⁺ )
[Production Example 40]

1- (4-Methoxyphenyl) -1- (2-morpholinoquinazolin-4-yl) ethanol (Compound Ia-40)
The title compound was obtained according to the method described in Preparation 39 using morpholine instead of piperidine.
¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, d, J = 8.5 Hz), 7.57-7.53 (1H, m), 7.45 (1H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.5 Hz), 6.98-6.95 (1H, m), 6.86 (2H, d, J = 8.5 Hz), 6.28 (1H, s), 4.02 (4H, t, J = 5.0 Hz), 3.88 (4H, t , J = 5.0 Hz), 3.80 (3H, s), 2.07 (3H, s).
FAB-Mass: 373 ((M + 1) ⁺ )
[Production Example 41]

1- (4-Methoxyphenyl) -1- [2- (4-methylpiperazin-1-yl) quinazolin-4-yl] ethanol (Compound Ia-41)
The title compound was obtained according to the method described in Preparation 39 using N-methylpiperazine instead of piperidine.
¹ H-NMR (CDCl ₃ ) δ: 7.58 (1H, d, J = 8.0 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.42 (1H, d, J = 7.5 Hz), 7.32 (2H, d, J = 8.0 Hz), 6.93 (1H, t, J = 7.5 Hz), 6.85 (2H, d, J = 8.5 Hz), 6.37 (1H, s), 4.06 (4H, t, J = 5.0 Hz) , 3.79 (3H, s), 2.58 (4H, t, J = 5.0 Hz), 2.40 (3H, s), 2.07 (3H, s).
FAB-Mass: 379 ((M + 1) ⁺ )
[Production Example 42]

1- (4-Methoxyphenyl) -1- {2- [4- (4-fluorophenyl) piperazin-1-yl] quinazolin-4-yl} ethanol (Compound Ia-42)
The title compound was obtained according to the method described in Production Example 39 using N- (4-fluorophenyl) piperazine instead of piperidine.
¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, d, J = 8.5 Hz), 7.54 (1H, t, J = 7.5 Hz), 7.44 (1H, d, J = 8.5 Hz), 7.33 (2H, d, J = 9.0 Hz), 7.04-6.94 (6H, m), 6.85 (2H, d, J = 9.0 Hz), 6.33 (1H, s), 4.19 (5H, t, J = 5.0 Hz), 3.79 ( 4H, s), 3.27 (5H, t, J = 5.0 Hz), 2.08 (4H, s).
FAB-Mass: 459 ((M + 1) ⁺ )
[Production Example 43]

1- (6,7-Dimethoxyquinazolin-4-yl) -1- (4-methoxyphenyl) ethanol (Compound Ia-43)
Using the compound w obtained in Reference Example 23 instead of the compound a, the title compound was obtained according to the method described in Production Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.13 (1H, s), 7.34 (2H, d, J = 9.0 Hz), 7.30 (1H, s), 6.91 (1H, s), 6.85 (2H, d, J = 9.0 Hz), 6.54 (1H, s), 3.99 (3H, s), 3.77 (2H, s), 3.62 (3H, s), 2.06 (3H, s).
FAB-Mass: 341 ((M + 1) ⁺ )
[Production Example 44]

1- (3,4-Dimethoxyphenyl) -1- (6,7-dimethoxyquinazolin-4-yl) ethanol (Compound Ia-44)
Using the compound x obtained in Reference Example 24 instead of the compound a, the title compound was obtained according to the method described in Production Example 1.
¹ H-NMR (CDCl ₃ ) δ: 9.16 (1H, s), 7.31 (1H, s), 7.10 (1H, d, J = 8.5 Hz), 6.96 (1H, s), 6.84 (1H, d, J = 8.5 Hz), 6.82 (1H, s), 6.48 (1H, s), 4.01 (3H, s), 3.86 (3H, s), 3.72 (3H, s), 3.63 (3H, s), 2.06 (3H , s).
FAB-Mass: 371 ((M + 1) ⁺ )
[Production Example 45]

1- (4-Methoxyphenyl) -2-phenyl-1- (2-phenylquinazolin-4-yl) ethanol (Compound Ia-45)
The compound g obtained in Reference Example 7 was used in place of Compound a, and benzylmagnesium bromide was used in place of methylmagnesium iodide to give the title compound according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 8.39-8.38 (2H, m), 8.10 (1H, d, J = 8.5 Hz), 7.98 (1H, d, J = 8.5 Hz), 7.82 (1H, t, J = 7.5 Hz), 7.52-7.51 (3H, m), 7.45-7.40 (3H, m), 7.01-6.97 (3H, m), 6.90 (2H, d, J = 8.5 Hz), 6.74 (2H, dd, J = 7.5 Hz, 2.0 Hz), 6.00 (1H, s), 4.01 (2H, s), 3.82 (3H, s).
FAB-Mass: 433 ((M + 1) ⁺ )
[Production Example 46]

1,2-diphenyl-1- (quinazolin-4-yl) ethanol (Compound Ia-46)
The title compound was obtained according to the method described in Production Example 1 using benzylmagnesium bromide instead of methylmagnesium iodide.
¹ H-NMR (CDCl ₃ ) δ: 9.09 (1H, s), 8.07 (1H, d, J = 8.5 Hz), 7.99 (1H, d, J = 8.5 Hz), 7.86-7.83 (1H, m), 7.49-7.46 (3H, m), 7.37 (2H, td, J = 7.5 Hz, 2.0 Hz), 7.32 (1H, tt, J = 7.5 Hz, 2.0 Hz), 7.09 (1H, t, J = 7.5 Hz) , 7.01 (2H, t, J = 7.5 Hz), 6.68 (2H, d, J = 7.0 Hz), 5.89 (1H, s), 3.98 (2H, s).
FAB-Mass: 327 ((M + 1) ⁺ )
[Production Example 47]

1- (4-Methoxyphenyl) -1- (4-methoxyquinazolin-2-yl) ethanol (Compound Ib-1)
Using the compound v obtained in Reference Example 22 instead of the compound a, the title compound was obtained according to the method described in Preparation Example 1.
¹ H-NMR (CDCl ₃ ) δ: 8.10 (1H, dd, J = 8.0 Hz, 1.4 Hz), 7.91 (1H, d, J = 8.5 Hz), 7.82-7.78 (1H, m), 7.71 (2H, d, J = 8.5 Hz), 7.55-7.49 (1H, m), 6.84 (2H, d, J = 8.5 Hz), 5.93 (1H, s), 4.18 (3H, s), 3.77 (3H, s), 2.04 (3H, s).
FAB-Mass: 311 ((M + 1) ⁺ )
[Reference Example 1]

4-Benzoylquinazoline (compound a)
To a suspension of 4-chloroquinazoline (329 mg, 2 mmol), benzaldehyde (254 mg, 2.4 mmol), 1,3-dimethylimidazolium iodide (23 mg, 0.1 mmol) in THF (20 mL), 60% sodium hydride (100 mg, 2.5 mmol) was added, and the mixture was refluxed and stirred for 1 hour under an argon atmosphere. The reaction mixture was poured into ice water, and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound (376 mg, 1.61 mmol) as colorless crystals in a yield of 80%.
¹ H-NMR (CDCl ₃ ) δ: 9.44 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz), 8.01-7.95 (4H, m), 7.70-7.65 (3H, m), 7.51 (2H, t, J = 7.6 Hz).
FAB-Mass: 235 ((M + 1) ⁺ )
[Reference Example 2]

4- (3-methoxybenzoyl) quinazoline (compound b)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 235 ((M + 1) ⁺ )
[Reference Example 3]

4- (3-Benzyloxybenzoyl) quinazoline (compound c)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 241 ((M + 1) ⁺ )
[Reference Example 4]

4- (4-Fluorobenzoyl) quinazoline (compound d)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 253 ((M + 1) ⁺ )
[Reference Example 5]

4- (4-Chlorobenzoyl) quinazoline (compound e)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 269 ((M + 1) ⁺ )
[Reference Example 6]

4- (4-trifluoromethylbenzoyl) quinazoline (compound f)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 303 ((M + 1) ⁺ )
[Reference Example 7]

4- (p-Anisoyl) quinazoline (Compound g)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 265 ((M + 1) ⁺ )
[Reference Example 8]

4- (4-Ethoxybenzoyl) quinazoline (compound h)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 279 ((M + 1) ⁺ )
[Reference Example 9]

4- (4-n-butoxybenzoyl) quinazoline (compound i)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 307 ((M + 1) ⁺ )
[Reference Example 10]

4- (4-trifluoromethoxybenzoyl) quinazoline (compound j)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 319 ((M + 1) ⁺ )
[Reference Example 11]

4- (4-Methylthiobenzoyl) quinazoline (compound k)
To a solution of 4- (4-fluorobenzoyl) quinazoline (126 mg, 0.5 mmol) in 1,4-dioxane (10 mL) was added dropwise a 15% sodium methanethiolate solution (2.0 mL), and the mixture was refluxed and stirred overnight. The reaction solution was allowed to cool and then poured into water, and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound (118 mg, 0.42 mmol) as yellow crystals in a yield of 84%.
¹ H-NMR (CDCl ₃ ) δ: 9.43 (1H, s), 8.17 (1H, d, J = 8.5 Hz), 8.08 (1H, d, J = 8.5 Hz), 8.01-7.98 (1H, m), 7.88 (2H, d, J = 8.5 Hz), 7.69-7.66 (1H, m), 7.30 (2H, d, J = 8.5 Hz), 2.54 (4H, s).
FAB-Mass: 281 ((M + 1) ⁺ )
[Reference Example 12]

4- (4-Methylaminobenzoyl) quinazoline (compound l)
The title compound was obtained according to the method of Reference Example 11.
FAB-Mass: 263 ((M + 1) ⁺ )
[Reference Example 13]

4- (4-Dimethylaminobenzoyl) quinazoline (compound m)
The title compound was obtained according to the method of Reference Example 11.
FAB-Mass: 278 ((M + 1) ⁺ )
[Reference Example 14]

4-piperoniloylquinazoline (compound n)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 279 ((M + 1) ⁺ )
[Reference Example 15]

4-veratroylquinazoline (compound o)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 295 ((M + 1) ⁺ )
[Reference Example 16]

4- (3,4,5-trimethoxybenzoyl) quinazoline (compound p)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 325 ((M + 1) ⁺ )
[Reference Example 17]

4- (p-anisoyl) -2-methylquinazoline (compound q)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 279 ((M + 1) ⁺ )
[Reference Example 18]

4- (p-Anisoyl) -2-phenylquinazoline (compound r)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 341 ((M + 1) ⁺ )
[Reference Example 19]

4- (p-Anisoyl) -2-trichloromethylquinazoline (compound s)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 382 ((M + 1) ⁺ )
[Reference Example 20]

4- (p-Anisoyl) -2-chloroquinazoline (compound t)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 299 ((M + 1) ⁺ )
[Reference Example 21]

2-Chloro-4-methoxyquinazoline (compound u)
To a solution of 2,4-dichloroquinazoline (398 mg, 2.0 mmol) in THF (15 mL) was added a 1M methanol solution of sodium methoxide (2.0 mL, 2.0 mmol), and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. After evaporating the solvent under reduced pressure, water and ethyl acetate were added to the residue to extract the product. The ethyl acetate layer was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to give the title compound (293 mg, 1.51 mmol) as a colorless oil in a yield of 75%.
¹ H-NMR (CDCl ₃ ) δ: 8.14 (1H, d, J = 7.9 Hz), 7.89-7.83 (2H, m), 7.57 (1H, ddd, J = 8.1 Hz, 6.3 Hz, 1.8 Hz), 4.24 (3H, s).
FAB-Mass: 195 ((M + 1) ⁺ )
[Reference Example 22]

2- (p-Anisoyl) -4-methoxyquinazoline (compound v)
The title compound was obtained from compound u and anisaldehyde obtained in Reference Example 21 according to the method of Reference Example 1.
FAB-Mass: 295 ((M + 1) ⁺ )
[Reference Example 23]

4- (p-anisoyl) -6,7-dimethoxyquinazoline (compound w)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 325 ((M + 1) ⁺ )
[Reference Example 24]

6,7-dimethoxy-4-veratroylquinazoline (compound x)
The title compound was obtained according to the method of Reference Example 1.
FAB-Mass: 387 ((M + 1) ⁺

The pharmaceutical composition containing the quinazoline compound of the present invention or a pharmacologically acceptable salt thereof has a cancer cell growth inhibitory activity and the like, and is used as an anticancer agent against various cancers. Can do.

Claims (11)

Formula (I)

{Where,
R ¹ is the same or different and is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic ring Group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl group, COR ¹¹ wherein R ¹¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic heterocyclic ring Group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted Represents an unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic alkyl group), COOR ¹² (wherein R ¹² is as defined above for R ¹¹ ), C (= Q ¹ ) NR ¹³ R ¹⁴ [wherein, Q ¹ represents an oxygen atom, a sulfur atom or NR ¹⁵ (wherein R ¹⁵ has the same meaning as R ¹¹ above), and R ¹³ and R ¹⁴ represent , Same or different, hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted Or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Aromatic heterocyclic alkyl group, ^{or, R 13} and ^{R 14} are taken together, represent a nitrogen-containing heterocyclic group], ^{OR 16 (wherein, R 16} is synonymous with the ^{R 11),} OCOR ¹⁷ (Wherein R ¹⁷ has the same meaning as R ¹¹ ), S (O) pR ¹⁸ (wherein p represents 0, 1 or 2 and R ¹⁸ has the same meaning as R ¹¹ ). , SO ₂ NR ¹⁹ R ²⁰ (wherein R ¹⁹ and R ²⁰ are the same or different and have the same meanings as R ¹³ and R ¹⁴ respectively), NR ²¹ R ²² [wherein R ²¹ and R ²² are , Same or different, hydrogen atom, substituted or unsubstituted alkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted Or an unsubstituted alicyclic compound An aromatic ring alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl group, COR ²³ (wherein R ²³ is wherein ^{R 11} as synonymous), in COOR ^{24 (wherein, R 24,} said ^{R 11} as _synonymous), SO ^{2 R 25 (wherein, R 25} is synonymous with the ^{R 11),} or , R ²¹ and R ²² together represent a nitrogen-containing heterocyclic group], N (R ²⁶ ) C (= Q ² ) NR ²⁷ R ²⁸ [wherein Q ² represents an oxygen atom, a sulfur atom, NR ²⁹ (wherein R ²⁹ is as defined above for R ¹¹ ), NCN, CHNO ₂ or C (CN) ₂ , R ²⁶ is as defined above for R ¹¹ , and R ²⁷ and R ²⁸ are , same or different, each of the ^{R 13} and ^{14 _{synonymous], N (R 30) SO}} 2 NR 31 R 32 ( ^{wherein, R 30} has the same meaning as the ^{R 11, R 31} and ^{R 32} are the same or different, each of said ^{R 13} And R ¹⁴ ), SiR ³³ R ³⁴ R ³⁵ (wherein R ³³ , R ³⁴ and R ³⁵ are the same or different and have the same meaning as R ¹¹ ), nitro group, cyano group or halogen Represents an atom,
R ² and R ^{3 each} have one group

(In the formula, Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or Unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted Or represents an unsubstituted aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl group)
And the other group has the same meaning as R ¹ ,
m represents an integer of 0 to 4}
Or a pharmacologically acceptable salt thereof as an active ingredient. The compound represented by the formula (I) is represented by the following formula (Ia)

(Wherein R ¹ , R ² , R ⁴ , Ar and m are as defined above)
The pharmaceutical composition according to claim 1, which is a quinazoline compound represented by the formula: The pharmaceutical composition according to claim 2, wherein Ar is a substituted phenyl group, and R ⁴ is a methyl group. The pharmaceutical composition according to claim 3, wherein the substituent of the substituted phenyl group is an alkoxy group or an alkylthio group. The pharmaceutical composition according to claim 4, wherein the alkoxy group is a methoxy group or an ethoxy group, and the alkylthio group is a methylthio group. 6. R ² is a hydrogen atom, a substituted or unsubstituted phenyl group, a furyl group, a trichloromethyl group, an alkoxy group, an alkylthio group, an allyloxy group, a dimethylamino group, a morpholino group, or a chloro group. A pharmaceutical composition according to any one of the above. The pharmaceutical composition according to claim 6, wherein the substituent of the substituted phenyl group is a chloro group, the alkoxy group is a methoxy group or an ethoxy group, and the alkylthio group is a methylthio group. The pharmaceutical composition according to claim ² , wherein R ¹ and R ² are hydrogen atoms, R ⁴ is a methyl group, and Ar is a 4-methoxyphenyl group. The compound represented by the formula (I) is represented by the following formula (Ib)

(Wherein R ¹ , R ³ , R ⁴ , Ar and m are as defined above)
The pharmaceutical composition according to claim 1, which is a quinazoline compound represented by the formula: A cell growth inhibitor containing the quinazoline compound represented by formula (I) according to any one of claims 1 to 9 or a pharmacologically acceptable salt thereof as an active ingredient. The cell growth inhibitor according to claim 10, wherein the cell is a cancer cell.